Effect of lipid emulsion on neuropsychiatric drug-induced toxicity: A narrative review

Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: “antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone” and “lipid emulsion or Intralipid.” Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%) > lipophilic drugs (8.3%) > suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.


Introduction
Currently, local anesthetic-induced systemic toxicity is treated with lipid emulsion, which is primarily used for parenteral nutrition. [1]Supportive treatments, which are used to alleviate central nervous and cardiovascular symptoms caused by toxicity due to other substances (including neuropsychiatric drugs without a specific antidote), include charcoal, gastric lavage, fluid administration, sodium bicarbonate, inotropic agents, vasopressors, anti-arrhythmic drugs, and defibrillation. [2,3][4] In 2008, Siriari et al [5] reported a clinical case regarding lipid emulsion resuscitation of intractable cardiac arrest due to toxic doses of bupropion (an antidepressant) and lamotrigine (an anticonvulsant); this was the first successful lipid emulsion resuscitation for nonlocal anesthetic toxicity.Antidepressants, including amitriptyline and fluoxetine, and antipsychotics, such as quetiapine and haloperidol, produce corrected QT interval (QTc) prolongation, which leads to Torsade de Pointes, ventricular fibrillation, and cardiac arrest. [6]SMOFlipid was reported to reverse the decreased Glasgow Coma Scale (GCS) score and QTc prolongation induced by clozapine (an atypical antipsychotic) toxicity. [7]Intralipid increased the GCS scores of patients with acute toxicity caused by various nonlocal anesthetic drugs. [8]In addition, the time required to recovery from sevoflurane and isoflurane anesthesia was shortened by lipid emulsion in rats, and appeared to be mediated by lipid emulsion-mediated reduction of sevoflurane and isoflurane concentrations. [9]However, a systemic analysis of case reports regarding the effect of lipid Hwang and Sohn • Medicine (2024) 103: 11  Medicine emulsion on neuropsychiatric drug-induced toxicity, including antidepressants, antipsychotics, benzodiazepines (sedatives), and anticonvulsants, has not previously been reported.Moreover, a randomized controlled study regarding the effect of lipid emulsion on neuropsychiatric drug-induced toxicity in humans is impossible due to ethics concerns. [10]Thus, in this review, we analyzed case reports on lipid emulsion treatment for neuropsychiatric drug-induced toxicity retrieved from PubMed until December 20, 2023.The goal of this review was to investigate the effect of lipid emulsion on symptoms caused by neuropsychiatric drug toxicity, with a particular focus on QTc prolongation, decreased GCS scores, and the lipophilicity of drugs that more frequently require lipid emulsion treatment.

Methods
Institutional review board approval was not needed because this was a narrative review using case reports.

Case search
Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, [11] the following terms were used to search for relevant case reports involving humans regarding the effect of lipid emulsion on drug toxicity caused by neuropsychiatric drugs until December 20, 2023: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid."We retrieved a total of 1185 articles from PubMed (Fig. 1), which is Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

Eligibility criteria
After removing duplicate articles (n = 374), 811 articles remained.A further 761 articles were excluded for the following reasons: no case report regarding lipid emulsion therapy, review article, systemic review, nonhuman cases, letter to the editor (not case report), and/or an original clinical and laboratory research article (Fig. 1).Finally, 50 articles were included in the analysis.As 1 article contained 2 patients and another article contained 10 patients, the 50 articles included 60 patients (Fig. 1).

Data extraction
Pre-and post-lipid emulsion treatment QTc intervals and GCS scores were obtained from each case report based on measurements just before and after the administration of lipid emulsion, respectively.QTc intervals were calculated using the Bazett formula (QTc = QT/RR 1/2 ). [6]All other data, including age, sex, underlying diseases, neuropsychiatric drugs, dosage, lipid emulsion treatment information, improvement of symptoms, and outcomes, were obtained from the case reports.Log P (octanol/ water partition coefficient) was obtained from PubChem. [12]

Statistical analysis
Normality tests for all data, which included log P of the drug, GCS score, and QTc, were performed using Shapiro-Wilk tests (Prism 5.0; GraphPad Software, San Diego, CA).The effect of lipid emulsion on GCS score was analyzed using Wilcoxon signed-rank tests.The effect of lipid emulsion on QTc prolongation was analyzed using paired Student's t tests.The log P values of the groups which required more than or less than 3 lipid emulsion treatments were compared using the Mann-Whitney test.P values below .05indicate statistical significance.

Posttreatment symptom recurrence
In some cases, symptoms initially improved following the administration of lipid emulsion but later deteriorated.These later-onset symptoms included altered mental status, a widened QRS interval, hypotension, pulseless wide-complex tachycardia, apnea, pupil dilation, decreased GCS scores, tachycardia, and somnolence.The drugs associated with these recurrent symptoms included bupropion, amitriptyline, fluoxetine, escitalopram, olanzapine, quetiapine, pregabalin, gabapentin, and propranolol.

Discussion
The results of this review show that administering lipid emulsion as an adjuvant drug shortens QTc prolongation and improves GCS scores in patients with intractable drug toxicity caused by toxic doses of lipid-soluble neuropsychiatric drugs, leading to improved recovery.Phase 3 of the cardiac action potential involves inactivation of inward calcium currents and activation of rapid outward potassium currents with slow potassium currents and inward rectifying potassium currents. [6]QT prolongation may occur when the outward potassium current is decreased or inward calcium or sodium currents is increased during phase 3 of the cardiac action potential. [6]Antidepressants (e.g., amitriptyline, fluoxetine, imipramine, and doxepine) and antipsychotics (e.g., quetiapine, haloperidol, chloropromazine, amisulpride, and risperidone) cause QT prolongation, leading to ventricular fibrillation and cardiac arrest. [6]Local anesthetic inhibits human ether-a-go-go-related gene cardiac potassium channels, which codes for rapid delayed rectified potassium channels. [63]upivacaine (log P: 3.41) is a highly lipid-soluble local anesthetic which induces QTc prolongation, and lipid emulsion reversed bupivacaine-related increased Tpeak-to-Tend intervals (transmural dispersion). [64]A randomized controlled study reported that lipid emulsion reversed clozapine (log P: 2.41) toxicity-related QTc prolongation. [7]In addition, lipid emulsion reversed QTc prolongation and inhibited myocardial cell death caused by amitriptyline toxicity in rats. [65]Similar to these previous reports, [7,64,65] lipid emulsion ameliorated QTc prolongation caused by toxic doses of neuropsychiatric drugs, including amitriptyline (log P: 4.92), trazodone (log P: 2.68), desulepin (log P: 4.49), haloperidol (log P: 4.3), lamotrigine (log P: 2.57), and quetiapine (log P: 2.81).The above-mentioned neuropsychiatric drugs (log P: 3.55 [2.65-4.59])are highly lipid-soluble (log P: >2; Table 1).In addition, lipid emulsion alone has positive inotropic and lusitropic effects. [66,67][65][66][67] However, retrospective analyses of case reports using lipid emulsion as an adjuvant drug have suggested that lipid emulsion does not significantly improve QTc prolongation caused by antihistamine diphenhydramine toxicity. [68]This difference may reflect the small sample size of the lipid emulsion group in the previous study, and differences in experimental methods (with vs without a control group).
Local anesthetic-related systemic toxicity usually involves the central nervous system, followed by symptoms associated with the cardiovascular system. [1]Early lipid emulsion administration in patients with bupivacaine-or ropivacaine-induced central nervous system symptoms prior to the onset of cardiac symptoms treated perioral numbness, restlessness, agitation, dizziness, and dysarthria. [69,70]In addition, a randomized controlled study suggested that lipid emulsion shortened the recovery time from isoflurane anesthesia, leading to improved recovery quality. [71,72]An animal study also corroborated that lipid emulsion shortened the time from isoflurane anesthesia to recovery, and decreased the proportion of the delta-band in the electroencephalogram during anesthesia, which appears to be mediated by lipid emulsion-induced reduction of isoflurane concentrations. [9]Lipid emulsion and supportive treatment improved the GCS of patients with drug toxicity due to nonlocal anesthetic drugs or clozapine alone. [7,8]Consistent with previous reports, [7,8,72] in our analysis, lipid emulsion reversed the decreased GCS score related to overdoses of the following: amitriptyline (log P: 4.92), trazodone (log P: 2.68), quetiapine (log P: 2.81), citalopram (log P: 3.76), bromazepam (log P: 2.05), fluoxetine (log P: 4.05), alprazolam (log P: 2.12), lamotrigine (log P: 2.57), and sertraline (log P: 5.51), which are all highly-soluble (log P: 3.38 ± 1.24).Moreover, lipid emulsion treatment in intravenous amitriptyline toxicity increased arterial plasma amitriptyline concentrations but reduced brain amitriptyline concentrations, suggesting lipid emulsioninduced sequestration of amitriptyline from the brain to the blood. [73]Thus, considering these previous laboratory reports, the increase in GCS after lipid emulsion administration may be associated with increased partitioning of highly lipid-soluble   neuropsychiatric drugs into the blood from the brain. [9,73]owever, further studies are needed to examine the detailed mechanism responsible for this phenomenon.
The magnitude of lipid emulsion-induced decreases in serum drug concentrations was reported to be strongly correlated with the lipid solubility of drugs. [74]Lipid emulsion inhibited the decreased blood pressure caused by toxic doses of verapamil, which has high lipid solubility (log P: 3.79), but had no effect on that caused by diltiazem, which has relatively low lipid solubility (log P: 2.8). [75]Moreover, lipid emulsion inhibited the decreased cell viability caused by verapamil toxicity in rat cardiomyoblasts more than that induced by diltiazem toxicity. [76]Lipid emulsion inhibited propranolol-induced hypotension, which is highly lipid-soluble (log P: 3.48). [77]owever, it exerted no effect on metoprolol-related hypotension, which is less lipid-soluble (log P: 2.15). [78][76][77][78] Lipid emulsion resuscitation is believed to be mediated by a lipid shuttle which forms via binding of the lipid emulsion to the offending drugs, allowing for their redistribution. [79]Intravenously-administered lipid emulsions generate a lipid phase component in the blood, which adsorbs lipidsoluble drugs from the heart and brain, which receive high blood flows. [79]The drug-containing lipid emulsion is then delivered to the liver, muscle, and adipose tissue for detoxification and storage. [79]When lipid emulsions were given 30 minutes after intravenous amitriptyline toxicity, amitriptyline concentrations in the heart and brain decreased while that in the arterial plasma increased, suggesting lipid emulsionmediated partitioning from organs with high blood flow to the arterial blood. [73]Consistent with previous reports, 71.79% (28/39) of drugs that underwent lipid emulsion treatment for neuropsychiatric drug toxicity were highly lipid-soluble (log P: >2). [62]Moreover, the lipid solubility (log P) of the drugs for the group which required more than 3 lipid emulsion treatments were higher than that of the group which required less than 3 lipid emulsion treatments (Fig. 3).[76][77][78] Furthermore, as the log P of all drugs to produce improved QTc and GCS was more than 2, the high lipid solubility of these drugs may have contributed to the recovery of 96.66% (58/60) of patients from neuropsychiatric drug toxicity by shortening QTc prolongation and increasing GCS score.Bolus administration of 1.5 mL/kg lipid emulsion (20%) followed by 0.25 mL/kg/ min continuous infusion of 20% lipid emulsion was most frequently employed (12/60, 20%), which is the recommended dosing regimen to treat local anesthetic-related systemic toxicity. [1]However, local anesthetic systemic toxicity mostly occurs via inadvertently intravenous administration, whereas neuropsychiatric drug toxicity most occurs via oral administration.Thus, the toxicokinetics of drug toxicity due to toxic doses of local anesthetic and nonlocal anesthetic drugs are different.Furthermore, intravenous lipid emulsion administered 30 minutes after amitriptyline toxicity via orogastric administration increased blood amitriptyline concentrations, suggesting lipid emulsion-induced increased absorption from the gastrointestinal tract. [80]Thus, further studies are needed to determine the optimal dosing regimen of lipid emulsion treatment for nonlocal anesthetic drug toxicity via oral administration.Studies have shown that 1% plasma triglyceride has both scavenging and positive inotropic and lusitropic effects. [66,67,81]n addition, the maximum Intralipid (10%) clearing capacity (K 1 ) has been reported to be 110 ± 4 μM/L/min.[82] One previous report suggested the following dosing regimen for 20% lipid emulsion treatment for nonlocal anesthetic drug toxicity via oral administration, which produced a 1% plasma triglyceride concentration: 1.5 mL/kg bolus administration, then 0.25 mL/kg/min continuous infusion for 3 minutes, followed by 0.025 mL/kg/min continuous infusion.[66,67,[80][81][82][83] Previous studies have suggested that lipid emulsion treatment improves various symptoms caused by nonlocal anesthetic drug toxicity in the following order of frequency: symptoms of the cardiovascular system alone > symptoms of the central nervous system alone > symptoms associated with both the cardiovascular and central nervous systems.[2,3] However, in the present study, lipid emulsion treatment most commonly improved symptoms associated with the cardiovascular and central nervous systems, followed by the cardiovascular system alone, followed by the central nervous system alone. Consistent with a previous report, the main reason for prescribing lipid emulsion treatment in neuropsychiatric drug toxicity was hemodynamic depression (53/60, 88.3%) that was resistant to supportive treatment.[2] A meta-analysis of lipid emulsion treatment for nonlocal anesthetic-induced toxicity reported that lipid emulsion treatment reduced the odds ratio of mortality to 0.43.[84] After lipid emulsion treatment, most patients (52/60, 86.6%) fully recovered from neuropsychiatric drug toxicity which was intractable to supportive treatment.Similar to previous reports, lipid emulsion treatment produced the following side effects: lipemia, adult respiratory distress syndrome, pancreatitis, and hypertriglyceridemia. [85,86] On the other hand, these side effects may be partially due to underlying conditions rather than lipid emulsion treatment itself (protopathic bias).[87] Consistent with previous reports, Intralipid was commonly used for the treatment of neuropsychiatric drug toxicity.[2,3] However, the availability of Intralipid is limited because linoleic acid, which is the main long-chain fatty acid in Intralipid, produces proinflammatory mediators and induces lipid perioxidation.[88] However, alternative lipid emulsion preparations can be used in the treatment of cardiovascular depression related to local anesthetic systemic toxicity, such as Lipofundin MCT/LCT, SMOFlipid, and Clinoelic.[89] Thus, other alternative lipid emulsions such as Lipofundin MCT/LCT, SMOFlipid, and Clinoelic, can be used as adjuvant drugs with supportive treatment in treating nonlocal anesthetic drug toxicity involving critical cardiovascular depression.In the current analysis, lipid emulsion administration led to full recovery from some cases of neuropsychiatric drug toxicity.However, other patients with toxicity induced by the same drug did not fully recover.These contrasting results may be due to the dosage of the neuropsychiatric drug, predisposing factors, lipid emulsion dosage, timing of lipid emulsion administration, and additional supportive treatments used.

Limitations of this study
We examined the effect of lipid emulsion as an adjuvant drug on toxicity related to various neuropsychiatric drugs.However, examining the effect of lipid emulsions on drug toxicity caused by a single antidepressant or antipsychotic is more appropriate for reaching clear conclusions.Second, negative results (no beneficial effect of supportive treatment plus lipid emulsion compared with supportive treatment alone) regarding lipid emulsion treatment of neuropsychiatric drug toxicity are relatively more difficult to publish compared with positive results, which skews the results of case-based analysis.Third, this analysis only used case reports of patients treated with both lipid emulsion and supportive treatment, and an analysis comparing lipid emulsion and supportive treatment with supportive treatment alone is needed to confirm our findings.Despite these limitations, our study results hold value as it is impossible to perform a completely randomized clinical study to examine the effects of lipid emulsions on drug toxicity in humans for various reasons, including ethical issues.In addition, several case reports regarding lipid emulsion treatment for neuropsychiatric drug toxicity are available.The present study is a comprehensive systemic review of case reports regarding lipid emulsion treatment for neuropsychiatric drug toxicity, with a particular focus on GCS scores, QTc, and the lipophilicity of the offending drugs.Thus, this analysis may be helpful in guiding lipid emulsion treatment for neuropsychiatric drug toxicity.Further analysis using additional case reports accumulated through the lipid emulsion resuscitation registry is needed to reach clearer conclusions.

Conclusions
Taken together, lipid emulsion treatment as an adjuvant drug induces the reversal of decreased GCS scores and QTc prolongation caused by toxic doses of highly lipid-soluble neuropsychiatric drugs (amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram) which are resistant to supportive treatment, leading to improved recovery from neuropsychiatric drug toxicity.However, more studies on large cohorts and analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation on neuropsychiatric drug toxicity and its underlying mechanisms.

Figure 1 .
Figure 1.Flow chart for retrieving clinical case reports on lipid emulsion treatment as an adjuvant therapy for systemic neuropsychiatric (antidepressants, antipsychotics, benzodiazepines, and anticonvulsants) drug toxicity based on a PubMed keyword search."n" indicates the number of articles.

Figure 2 .
Figure 2. Distribution of lipid solubility (log P: log [octanol/water partition coefficient]) of neuropsychiatric drugs (total number of drugs: 39) that caused toxicity in patients undergoing lipid emulsion treatment.N/A = not available.

Figure 3 .
Figure 3.Comparison of lipid solubility (log P: log [octanol/water partition coefficient]) for the groups (including duplicates) that required more than or less than 3 lipid emulsion treatments; the total numbers of drugs in each group were 75 and 33, respectively.Data are shown as the median ± interquartile range (25-75%); ***P < .001vs group which required less than 3 lipid emulsion treatments.

Figure 4 .
Figure 4. Effect of lipid emulsion on the GCS scores in patients (n = 12) undergoing lipid emulsion treatment for neuropsychiatric drug toxicity.Data are shown as the median ± interquartile range (25-75%); n indicates the number of patients and **P = .0037vs before lipid emulsion treatment.GCS = Glasgow Coma Scale.

Figure 5 .
Figure 5.Effect of lipid emulsion on the prolonged corrected QTc interval (QTc) in patients undergoing lipid emulsion treatment for drug toxicity related to a single neuropsychiatric drug (A, n = 11) or single and multiple drugs (B, n = 16).Data are shown as the mean ± standard deviation; n indicates the number of patients.***P < .001vs before lipid emulsion treatment.